Margareta Mikkelsen

An (11;21) Translocation in Four Generations with Chromosome 11 Abnormalities in the Offspring

A family in which a translocation t(11; 21) (q23 ;q22) was segregating through three generations was studied clinically and cytogenetically. Individuals mono somic for the distal part of the long arm

Paternal age effect in Down's syndrome.

Increasing incidence of Downs syndrome with advancing paternal age for given maternal age has been demonstrated. Comparisons are made between an almost complete Downs syndrome sample from the Copenhagen Metropolitan Area and a randomly selected sample of births from the same area and the same time period. Men above 55 years have a significantly increased risk of getting children with Downs syndrome.

Incidence study of Down's syndrome in Copenhagen, 1960-1971; with chromosome investigation.

The aim of the study was to obtain incidence figures for Downs syndrome throughout a period where a considerable change in the age distribution of child-bearing mothers has taken place and to study if the expected fall in incidence has occurred. In parts of the Copenhagen Metropolitan area 235 liveborn patients with Downs syndrome were ascertained in the period 1960 to 1971 in a population of 1-2 million with a total of 204771 births. All patients available were examined cytogenetically (75%). In 160 (90-4%) a regular trisomy 21 was observed. In 6-2% of the cases translocations and in 2-3% of the cases mosaics were found. Two double trisomies and a double trisomy mosaic were observed. Throughout the period 1960-71 the percentage of women over 30 years delivering children decreased from 23-4% in the beginning of the period to 16-2% at the end of the period. In the first part of the period 52-6% of the cases were born to mothers over 30, at the end of the period 40% of Downs syndrome mothers were of that age. However, the incidence was unchanged throughout the whole period, about 1-15 per 1000 births. For some age groups a steady rise in incidence of trisomy 21 cases was found throughout the whole period. These findings may be explained by better ascertainment of patients at the end of the period; however, environmental factors may also play a role.

Possible Localization of Gc-System on Chromosome 4. Loss of Long Arm 4 Material Associated with Father-Child Incompatibility Within the Gc-System

A mentally retarded girl with a sporadically occurring B/F translocation was reexamined with new banding techniques. Chromosome material from the long arm of chromosome 4 was inserted into the long arm of chromosome 20. The segment 4q11 leads to q13 was lost. The formerly reported abnormal segregation of the Gc-system was verified. The localization of the Gc-locus on the lost segment cannot be ruled out.

X-Linked mental retardation with fragile X. a pedigree showing transmission by apparently unaffected males and partial expression in female carriers

SummaryA large family is reported in which mental retardation associated with the fragile site at Xq28 was found. Three normal males seemed to have transmitted the trait through their daughters to affected grandchildren.A total of 19 family members were investigated cytogenetically. Mentally retarded males showed macroorchidism and the fragile X. Three mentally retarded females were found, with the fragile X in a high percentage of cells; in contrast, the obligate carriers showed no or only few cells with the fragile X.

Apolipoprotein E allele distribution in parents of Down's syndrome children.

BACKGROUND An increased risk of Alzheimers disease (AD) has been reported in young mothers of Downs syndrome (DS) probands. Allele epsilon4 of the apolipoprotein E (apoE) gene is a genetic susceptibility factor for AD. We examined the distribution of apoE alleles in people with DS and their parents. METHODS We studied 188 Danish people with non-mosaic free trisomy 21 of known parental origin (determined by DNA polymorphism analysis), and their parents, chosen from a population-based study of DS, and compared the frequency of apoE alleles with a previously published Danish control sample. FINDINGS In people with DS, there was no significant difference in apoE allele distribution compared with controls. The frequency of allele epsilon4 in the fathers (11.8%) was significantly lower than in controls (17.4%, p=0.02). The frequency of allele epsilon4 in the mothers (19.4%) was not significantly different from that of controls. Nevertheless, in young mothers with a meiosis II error, epsilon4 frequency was 30.0%, significantly higher than in older mothers with a meiosis II error (13.0%, p=0.03). INTERPRETATION We suggest that apoE allele epsilon4 is a risk factor for meiosis II non-disjunction in young mothers, but the biological role of apoE in oocytes remains to be investigated.

Linkage studies of X-linked mental retardation: High frequency of recombination in the telomeric region of the human X chromosome (fragile site/linkage/recombination/X chromosome)

SummaryOne of the commonest forms of X-linked mental retardation is associated with a fragile site at Xq27 on the human X chromosome which can be visualised structurally after culturing cells in folate-deficient media. Unusually, the mutation can be transmitted through a phenotypically normal male. There is already some evidence that the gene loci for G6PD and factor IX are linked to this mental retardation locus. We have followed the inheritance of a DNA sequence 52A, in fragile site families that are also informative for factor IX. We demonstrate that these probes are localised at Xq27/Xq28-Xqter, close physically to the fragile site. We did not find close linkage between 52A, factor IX, and the fragile site in the families studied despite 52A and factor IX showing linkage in normal families. We discuss the importance of these data for the genetic mapping of this region of the human X chromosome and the implication for the use of these DNA probes for clinical diagnosis.

Maternal and paternal origin of extra chromosome in trisomy 21.

SummaryFluorescence markers were studied in 40 patients with Downs syndrome and their parents. In 11 cases maternal and in 5 cases paternal non-disjunction could be shown. The disjunctional event occurred in the first meiotic division in 5 maternal and in 2 paternal cases. A second division failure was found in 4 maternal and 2 paternal cases. In 3 cases the failure could either be of first or second meiotic division origin.

(6;15) Translocation with loss of chromosome material in the patient and various chromosome aberrations in family members

SummaryA translocation of the long arm of chromosome No. 15 onto the long arm of chromosome No. 6 was observed in a severely mentally and physically retarded patient with a peculiar appearance. Fluorescence and Giemsa banding showed loss of chromosomal material from the distal part of chromosome No.6; 45,XY,tan(6;15) (6pter→6q25::15q12→15pter). The probands father and brothers showed hyperdiploid cells and cells with rearrangements. Regular Downs syndrome was observed in a first cousin once removed.ZusammenfassungBei einem oligophrenen Patienten mit eigentümlichem Aussehen wurde eine Translokation des langen Armes von Chromosom 15 am langen Arm des Chromosoms 6 gefunden. Fluorescenzstudien und Giemsabandfärbung zeigten, daß Chromosomenmaterial vom distalen Teil des langen Arms des Chromosomes 6 verlorengegangen war; 45,XY,tan(6;15) (6pter→6q25::15q12→15pter). Beim Vater und zwei Brüdern wurden hyperdiploide Zellen und Rearrangements, bei einem Vetter eine Trisomie 21 (Down-Syndrom) gefunden.

Carrier detection and X-inactivation studies in the fragile X syndrome

SummaryCytogenetic investigations by three different lymphocyte culture methods in 63 obligate and potential carriers of the fragile X [fra(X)] are reported. A difference was observed between normal and retarded carriers in the manifestation of the fra(X). An inverse relationship between percentage positive cells and age was demonstrated in normal carriers, whereas retarded carriers generally showed higher percentages at all ages. X-inactivation studies in retarded carriers compared with normal carriers showed a tendency towards a skewed inactivation pattern with an excess of early replicating fra(X) in both groups when carriers expressing high percentages of fra(X) positive cells were compared. In normal carriers with low percentage expression the tendency was apparently reversed. The relationship between the replication pattern of the fragile X and the mental status of the individual is more complicated than suggested by previous studies.